Progression of HIV-associated neurocognitive disorders (HAND) is associated with trafficking of human immunodeficiency virus type-1 (HIV) infected leukocytes into the central nervous system (CNS), which appears to begin as early as 8 days post-infection. However, at this time the cerebrospinal fluid (CSF) levels of MCP- 1/CCL2 were found to be unchanged, thus making it challenging to explain how HIV-infected leukocytes are mobilized during this early stage of infection, which leads to the establishment of CNS reservoirs. Interestingly, our supporting data reveal that these early events noted in acutely infected individuals can be closely mimicked in HIV-infected humanized mice. Importantly, we observed marked platelet activation in these mice within 1 to 4 weeks of infection -as reported in persons with acute HIV infection-which was tightly correlated with the rate of human peripheral leukocytes migration into the CNS. Based on these findings, we posit that HIV triggers a push and pull mechanism throughout the course of infection that enables trafficking of infected leukocytes into the CNS. In this model, we propose that the activated platelets initially provide a push by directly interacting with infected leukocytes to facilitate migrationof leukocytes across the blood-brain barrier (BBB). This follows with a rapid increase in the production of chemokines within the CNS thus establishing a complementing pull that recruits additional infected/activated leukocytes into the CNS. This model then, in full accordance with the available literature, accounts for how neuroinflammation is initiated, and maintained, in HIV-infected individuals. These studies will bring together five established investigators and one emerging investigator with proven expertise in virology, platelet/monocyte biology, animal models of HIV-infection, therapeutics, and HIV clinical research. Importantly, proposed studies will leverage research infrastructure offered by the University of Rochester Center for AIDS Research (UR-CFAR). Our studies contain great potential for clinical translation, in which, our investigations will reveal how early intervention may impact viral reservoirs in the CNS, and how a two-prong approach in which targeting viral entry into the CNS while dampening secondary inflammation would yield long-term neuroprotection and tissue homeostasis.